The present invention relates to novel and useful prostaglandins and to a chemical process for preparing same. More particularly, the invention pertains to new prostaglandin compounds represented by Formula 1 of the following general formula: ##STR2## wherein R.sub.1 is a member selected from the group consisting of hydrogen and lower alkyl, R.sub.2 is a member selected from the group consisting of hydrogen and acyl of 1 to 18 carbon atoms inclusive, the diastereomers and the non-toxic, pharmaceutically acceptable salts. The compounds are prepared from naturally occurring prostaglandins by the selective hydrogenation of carbon to carbon double bonds followed by epimerization of biologically inactive groups to biologically active groups and by the reaction of carboxyl groups and hydroxyl groups with saltifying and esterifying agents to produce the novel compounds of Formula 1. The compounds of Formula 1 are useful as antihypertensive agents and also as intermediates for preparing other prostaglandins possessing therapeutic properties.
In the present disclosure and the accompanying claims the definitions of symbols and terms in the foregoing formula and where they appear elsewhere throughout this specification and the accompanying claims, their usage thereof has the following significance:
By "lower alkyl" is meant straight or branched chain alkyl radicals of 1 to 8 carbon atoms inclusive, such as, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, pentyl, neo-pentyl, n-hexyl, iso-hexyl, heptyl, n-octyl, 4,4-dimethyl pentyl, 2-ethyl hexyl, 2,2,4-trimethylpentyl, and the like.
Exemplary of "acyl" groups are the acyl groups having from 1 to 18 carbon atoms inclusive such as alkanoyl, alkenoyl, aroyl, substituted derivatives thereof, and the like. Typical alkanoyl groups include formyl, valeryl, acetyl, propionyl, heptanoyl, actanoyl, undecanoyl, lauroyl, palmitoyl, stearoyl, oleoyl, isomeric forms thereof, and the like; typical alkenoyl groups include acryloyl, methacryloyl, crotonyl, 3-butenoyl, .beta.-methyl-.alpha.-butenoyl, and the like; typical aroyl groups such as benzoyl, phenylacetyl, cinnamoyl, naphthoyl, p-ethoxybenzyl, allyloxyphenylacetyl, and the like. Examples of other acyl moieties within the scope of the invention are carboxacyl moieties such as cyclohexanecarbonyl, 3-cyclohexanecarbonyl, p-chlorophenoxyacetyl, succinyl, p-nitrobenzoyl, furoyl, 3-pyridinecarbonyl, and the like.
The phrase "pharmaceutically acceptable" or "non-toxic salts" as used herein generally includes the non-toxic alkali metal and the non-toxic alkaline earth bases such as sodium, potassium, calcium, lithium, copper and magnesium, the hydroxides and the carbonates thereof, the ammonium salts and the substituted ammonium salts, for example, the non-toxic salts of trialkylamines such as triethylamine, trimethylamine, tri-isopropylamine, tri-n-propylamine, tri-n-butylamine, and other amines such as morpholine, diethylamine, dimethylamine, methyl-cyclohexylamine, ethylcyclohexylamine, glucosamine, procaine, dibenzylamine, triethanolamine, N-benzyl-.beta.-phenylethylamine, ethyldimethylamine, tripropanolamine, N-benzyl-.beta.-phenylmethylamine, ethyldipropylamine, ethyldiisopropylamine, benzylamine, p-ethoxybenzylamine, N-(lower)alkyl piperidines, such as N-ethylpiperidine, N-isopropylpiperidine, N-methylpiperidine and other pharmaceutically acceptable amines. Also, the non-toxic salts of Formula 1 with monoalkyl and dialkylamines, and tetra-alkylammonium hydroxides. The latter are art called therapeutically acceptable quaternary ammonium salts.
The numbering system and the stereochemistry nomenclature used for the prostaglandin compounds of this invention is the art accepted numbering and nomenclature. That is, the cyclopentane ring of the prostenoic acid is numbered 8 through 12 inclusive for a 20 carbon naturally occurring or synthetic prostaglandin. The carboxyl side chain or its derivatives (R.sub.1 .dbd.H or alkyl) is bonded to the cyclopentane ring at the ring's 8 position, and the alkyl side chain is bonded to the cyclopentane ring at the ring's 12 position. The stereochemistry of the substituents on the cyclopentane ring, when shown, may be .alpha.-oriented or .beta.-oriented, that is, .alpha.-substituents are oriented on the same side of the cyclopentane ring as the carboxyl side chain, and .beta.-substituents are oriented in the opposite sense or on the same side as the alkyl side chain. The substituents bonded to the alkyl side chain may have a sinister (S) or rectus (R) configuration which is equivalent to .alpha. and .beta. respectively, in the projection formula used here. In the formulae used herein, a broken line indicates an .alpha.-configuration, a solid wedge indicates a .beta.-configuration and a wavy line indicates that these substituents are in the .alpha.-configuration or the .beta.-configuration. The numbering system and stereochemistry is reported in Progess in the Chemistry of Fats and Other Lipids, Vol IX, pages 233 to 236, Pergamon Press, New York; and, J. Lipids Research, Vol. 10, pages 316 to 319, 1969.